Information on the following diseases can be found in the Related Disorders section of this report:

• Very Long-Chain Acyl-CoA Dehydrogenase (VLCAD) Deficiency; LCAD-VLCAD Deficiency included
• Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency
• Short-Chain Acyl-CoA Dehydrogenase (SCAD) Deficiency
• Glutaricaciduria II (GA II)
• Additional Metabolic Disorders (General)
• Reye Syndrome

Children with early-onset VLCAD-C present with symptoms within days or weeks after birth. These infants also show signs of low blood sugar (hypoglycemia), irritability and listlessness (lethargy). From ages two or three months to about two years, infants with this form of the disorder will be at risk for thickening of the heart muscles (hypertrophic cardiomyopathy), abnormal heart rhythms and cardiorespiratory failure.

Later-onset VLCAD-H may present with recurrent episodes of lethargy and even coma associated with low blood sugar during infancy and a noticeably enlarged liver (hepatomegaly) during childhood. During the teen years and early adulthood, the patient usually experiences periodic attacks of hypoglycemia and lethargy.

The hypoglycemia associated with each form occurs with little or no accumulation of ketone bodies (hypoketotic hypoglycemia) in the blood. (Ketone bodies are chemical substances normally produced by fatty acid metabolism in the liver.)

There are very complicated patterns of blood gases and concentrations of unusual acids in the blood. A patient’s blood will be examined for these patterns if VLCAD is suspected.
Affected individuals may begin to experience recurrent increased acid levels in blood and body tissues (metabolic acidosis); sudden cessation of breathing (respiratory arrest) and even cardiac arrest. These symptoms may be associated with cardiomyopathy [see below]); listlessness, severe drowsiness (lethargy), and coma. Without prompt, appropriate treatment, such acute episodes may lead to potentially life-threatening complications. (For further information, please see Standard Therapies below.)

Those with VLCAD deficiency may also present with fat deposits (fatty infiltration) and abnormal enlargement of the liver (hepatomegaly); poor muscle tone (hypotonia); and/or evidence of cardiomyopathy. For example, there may be abnormal thickening (hypertrophy) or stretching and enlargement (dilation) of the left lower chamber (ventricle) of the heart (i.e., hypertrophic or dilated cardiomyopathy). Cardiomyopathy may lead to weakening in the force of heart contractions, decreased efficiency in the circulation of blood through the lungs and to the rest of the body (heart failure), and various associated symptoms that may depend upon the nature and severity of the condition, patient age, and other factors.

VLCAD deficiency is usually associated with episodic hypoglycemia and inappropriately low ketone concentrations in the urine (impaired ketogenesis). Additional characteristic laboratory features include elevated levels of certain organic acids in the urine (dicarboxylic aciduria), increased levels of particular liver enzymes, secondary carnitine deficiency, and other findings.
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Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is transmitted as an autosomal recessive trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.

In the case of VLCAD, the genetic picture is more complicated than usual. There appear to be two faulty genes. One has been tracked to Gene Map Locus 17p11.2-p11.1 and the other, associated originally with long chain Acyl-CoA dehydrogenase deficiency (LCAD), at 2q34-q35. Since most experts now agree that LCAD is not an independent entity but a kind of VLCAD, the gene in question must play a role in the genetics of VLCAD.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22, and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 17p11.2-p11.1" refers to a region between bands 11.2 and 11.1 on the short arm of chromosome 17. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

As noted above, VLCAD deficiency is a genetic disorder of fatty acid metabolism. Metabolic disorders result from abnormal structure and functioning of a specific protein or enzyme. Enzymes are proteins that speed up the chemical reactions of the body. Enzymes are complicated proteins that must be folded in very precise ways in order to do their job of speeding up specific chemical reactions so that metabolism may proceed.
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Very long-chain acyl-CoA dehydrogenase deficiency is a rare metabolic disorder that was originally described in 1992. The introduction of heel-stick tandem mass spectrometry for the early diagnosis of VLCAD in newborns has markedly increased the number of infants in which the disorder is detected.

A publication of the Illinois Department of Public Health estimates the incidence of VLCAD at one per 50,000 live births.
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Symptoms of the following disorders may be similar to those of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. Comparisons may be useful for a differential diagnosis:

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is considered the most common of the fatty acid oxidation disorders. It is characterized by deficiency of an enzyme that acts on medium-chain length fatty acids. During infancy or early childhood, affected individuals typically begin to experience acute, recurrent episodes provoked by prolonged fasting. Episodes may be characterized by elevated acid levels in blood and body tissues (metabolic acidosis), hypoketotic hypoglycemia, vomiting, lethargy, coma, and/or cardiorespiratory arrest. Additional findings may include fatty infiltration of the liver, secondary carnitine deficiency, elevated levels of certain organic acids in the urine, and other abnormalities. MCAD deficiency is inherited as an autosomal recessive trait. (For more information on this disorder, choose “medium chain” or “MCAD” as your search term in the Rare Disease Database.)

Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is a rare disorder of fatty metabolism characterized by deficiency of an enzyme that acts on short-chain length fatty acids. Although associated symptoms and findings may be variable, most affected individuals have chronically elevated acid levels in the blood and body tissues (chronic acidosis), progressive skeletal muscle weakness, failure to grow and gain weight at the expected rate (failure to thrive), developmental delays, secondary carnitine deficiency, and elevated levels of certain organic acids in the urine. SCAD deficiency is transmitted as an autosomal recessive trait. (For more information on this disorder, choose "short chain" or "SCAD" as your search term in the Rare Disease Database.)

Glutaricaciduria II (GA II) is a metabolic disorder characterized by deficiency of either of two enzymes (i.e., electron transfer flavoprotein or electron transfer flavoprotein dehydrogenase). Symptoms and findings may be variable, with decreased disease severity appearing to correlate with increased age at symptom onset. In the neonatal period, associated abnormalities may include metabolic acidosis, hypoglycemia, elevated levels of multiple organic acids in the urine, an unusual odor of “sweaty feet,” poor muscle tone (hypotonia), enlargement of the liver (hepatomegaly), cardiomyopathy, and coma. In some of these cases, affected infants may also have facial abnormalities and multiple cysts in the kidneys. Later-onset disease may be associated with fasting-induced episodes characterized by hypoketotic hypoglycemia, metabolic acidosis, lethargy, coma, secondary carnitine deficiency, and/or other associated abnormalities. Glutaricaciduria II is inherited as an autosomal recessive trait. (For more information on this disorder, choose "glutaricaciduria II" as your search term in the Rare Disease Database.)

There are additional fatty acid oxidation disorders and other inborn errors of metabolism that may be characterized by certain symptoms and findings similar to those potentially associated with VLCAD deficiency. (For more information on these disorders, choose the exact disease name in question as your search term in the Rare Disease Database.)

Reye syndrome is a rare disorder that predominantly affects children from approximately age four to 12 years. In some cases, Reye syndrome has initially been suspected in infants or children with fatty acid oxidation disorders, including VLCAD deficiency. Reye syndrome is primarily characterized by rapid accumulation of fat in the liver and sudden inflammation and swelling of the brain (acute encephalopathy). Associated symptoms and findings may include the sudden onset of severe, persistent vomiting; elevated levels of certain liver enzymes in the blood (hepatic transaminases); severe disorientation; episodes of uncontrolled electrical disturbances in the brain (seizures); and coma. The condition’s cause is unknown. However, there appears to be an association between the onset of Reye syndrome and the use of aspirin-containing medications (salicylates) in children or adolescents with certain viral illnesses, particularly upper respiratory tract infections (e.g., influenza B) or, in some cases, chickenpox (varicella). Due to the potential association between the use of aspirin-containing agents and the development of Reye syndrome, it is advised that such medications be avoided for infants, children, adolescents, and young adults affected by viral infections such as influenza or chickenpox. (For further information, use "Reye" as your search term in the Rare Disease Database.)
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VLCAD deficiency may be diagnosed based upon a thorough clinical evaluation; identification of characteristic findings (e.g., hypoketotic hypoglycemia, severe skeletal muscle weakness, heart enlargement); and the results of various specialized tests, including analysis conducted on various specimens, such as urine, blood, muscle, liver tissue, skin cells (cultured fibroblasts), and/or white blood cells (leukocytes). A thorough and complete family history is especially important in order to determine if there is an episode of sudden infant death (SID) in the family’s past. One estimate has it that VLCAD makes up about 5% of all SID deaths.

In individuals with the disorder, urine organic acid analysis typically reveals reduced or absent ketone bodies and elevated levels of certain dicarboxylic acids (i.e., dicarboxylic aciduria, e.g., increased C6-C10, C12-C14 dicarboxylic acids). In some cases, there may be increased blood levels of the enzyme creatine phosphokinase (CPK) and the abnormal presence of myoglobin in the urine (myoglobinuria).
Removal (biopsy) and microscopic evaluation of small samples of liver tissue may also reveal fatty infiltration and structural changes of mitochondria. In addition, abnormal enlargement of the heart (cardiomegaly) associated with cardiomyopathy may be apparent upon chest x-ray examination.

Prenatal diagnosis is available by enzyme measurement of either cultured cells or cells obtained from the amniotic fluid or during chorionic villus sampling (CVS). (With amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta.)

Treatment
Disease management and treatment are primarily directed toward preventing and controlling acute episodes. Preventive measures include avoiding fasting for more than 10 to 12 hours and maintaining a low-fat, high-carbohydrate diet, with frequent feeding (i.e., to keep periods of fasting to a minimum). Additional recommendations may include the use of low-fat nutritional supplements, medium-chain triglycerides (e.g., MCT oil), and corn starch (e.g., at bedtime). Physicians may also advise supplementation with carnitine (Carnitor) and/or riboflavin.

If hospitalized for an acute episode, treatment may require the prompt administration of intravenous glucose (10% dextrose) and additional supportive measures as necessary.
Genetic counseling will also be of benefit for affected individuals and their families. In addition, as noted above, diagnostic testing of siblings is crucial to help detect and appropriately manage the condition. Other treatment for this disorder is symptomatic and supportive.

Researchers are studying heart blood flow and fatty acid metabolism using positron emission tomography (PET) scanning in individuals with inherited or acquired heart problems (cardiomyopathy). For more information, contact:

Dr. Daphne Hsu
Division of Pediatric Cardiology
(212) 305-6575

or

Dr. Steven Bergmann
Division of Cardiology
(212) 305-7594

or

Melanie Phipps, R.N.
(212) 305-0897

NORD does not promote, endorse, or encourage participation in any specific medical research study. This information is presented to further scientific understanding that could lead to the prevention, treatment, and/or cure of rare disorders. NORD recommends that anyone interested in participating in a clinical research program seek the advice or counsel of his or her own personal physician(s).

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Acyl-CoA Dehydrogenase, Very Long-Chain, Deficiency of. Entry Number; 201475: Last Edit Date; 6/13/2002.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Acyl-CoA Dehydrogenase, Long-Chain, Deficiency of. Entry Number; 201460: Last Edit Date; 4/30/2002.

TEXTBOOKS
Eaton S. Very Long-Chain Acyl-CoA Dehydrogenase Deficiency. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:439-40.

Behrman RE, et al., eds. Nelson Textbook of Pediatrics. 16th ed. Philadelphia, Pa: W.B. Saunders Company; 2000:377-80.

Lyon G, et al., eds. Neurology of Hereditary Metabolic Diseases in Children. 2nd ed. New York, NY: McGraw-Hill Companies, Inc.; 1996:28.

Roe CR, Ding J. Mitochondrial Fatty Acid Oxidation Disorders. In: Scriver CR, Beaudet AL, Sly WS, et al. Eds. The Metabolic Molecular Basis of Inherited Disease. 8th ed. McGraw-Hill Companies. New York, NY; 2001:2297-326.

REVIEW ARTICLES
Gregersen N, Andresen BS, Corydon MJ, et al. Mutation analysis in mitochondrial fatty acid oxidation defects: Exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype-phenotype relationship. Hum Mutat. 2001;18:169-89.

Gregersen N. Andresen BS, Bross P. Prevalent mutations in fatty acid oxidation disorders: diagnostic considerations. Eur J Pediatr. 2000;159 Suppl 3:S213-18.

Gregersen N, Bross P, Jorgensen MM, et al. Defective folding and rapid degradation of mutant proteins is a common disease mechanism in genetic disorders. J Inherit Metab Dis. 2000;23:441-47.

Vockley J, Rinaldo P, Bennett MJ, et al. Synergistic heterozygosity: disease resulting from multiple partial defects in one or more metabolic pathways. Mol Genet Metab. 2000;71:10-18.

JOURNAL ARTICLES
Shigematsu Y, Hirano S, Hata I, et al. Selective screening for fatty acid oxidation disorders by tandem mass spectrometry: difficulties in practical discrimination. J Chromatograph B Analyt Technol Biomed Life Sci. 2003;792:63-72.

Kluge S, Kuhnelt P, Block A, et al. A young woman with persistent hypoglycemia, rhabdomyolysis, and coma: recognizing fatty acid oxidation defects in adults. Crit Care Med. 2003;31:1273-76.

Solis JO, Singh RH. Management of fatty acid oxidation disorders: a survey of current treatment strategies. J Am Diet Assoc. 2002;102:1800-03.

Wilcox RL, Nelson CC, Stenzel P, et al. Postmortem screening for fatty acid oxidation disorders by analysis of Guthrie cards by tandem mass spectrometry in sudden unexpected death in infancy. J Pediatr. 2002;141:833-36.

Spiekerkoetter U, Tenenbaum T, Heusch A, et al. Cardiomyopathy and Pericardial Effusion Point to a Fatty Acid b-Oxidation Defect after exclusion of an Underlying Infection. Pediatr Cardiol. 2003;24:295-97.

Boles RG. Very long-chain acyl CoA dehydrogenase deficiency in an infant presenting with massive hepatomegaly. J Inherit Metab Dis. 2002;25:315-16.

Marsden D, Nyhan WL, Barshop BA. Creatine kinase and uric acid: early warning for metabolic imbalance resulting from disorders of fatty acid oxidation. Eur J Pediatr. 2001;160:599-602.

Zytkovicz TH, Fitzgerald EF, Marsden D, et al. Tandem mass spectroscopic analysis for amino, organic and fatty acid disorders in newborn dried blood spots: a two-year summary from the New England Newborn Screening Program. Clin Chem. 2001;47:1945-55.

Wood JC, Magera MJ, Rinaldo P, et al. Diagnosis of very long-chain acyl-CoA dehydrogenase deficiency from an infant’s newborn screening card. Pediatrics. 2001;108:E19.

Touma EH, Rashed MS, Vianey-Saban C, et al. A severe genotype with favorable outcome in very long-chain acyl-CoA dehydrogenase deficiency . Arch Dis Child. 2001;84:58-60.

Roe CR, Wiltse HE, Sweetman L, et al. Death caused by perioperative fasting and sedation in a child with unrecognized very long-chain acyl-CoA dehydrogenase deficiency. J Pediatr. 2000;136:397-99.

Scholte HR, Van Coster RN, de Jonge PC, et al. Myopathy in very long-chain acyl-CoA dehydrogenase deficiency: clinical and biochemical differences with fatal cardiac phenotype. Neuromuscul Disord. 1999;9:313-19.

Very-Long-Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD). Save Babies. Revised 7/9/03. 2pp.
www.savebabies.org/diseasedescriptions/vlcad.htm

FODs Defined. All In This Together. FOD Support Organization. nd. 10pp.
www.fodsupport.org/fods_defined.htm

Vianey-Saban C. Acyl-CoA dehydrogenase, very long chain, deficiency of. Orphannet. Jan 2000. 2pp.
www.orpha.net/consor/cgi-bin/pages/printer.php

Very long-chain acyl dehydrogenase deficiency. Expanded Newborn Screening Using MS/MS. nd. 1p.
www.newbornscreening.info/FELSI/health_care/index.php?pg=h_faq_type27

MCAD and Other fatty Acid Oxidation Disorders. Newborn Screening Program. Illinois department of Public Health. nd. 4pp.
www.idph.state.il.us/HealthWellness/fs/mcad.htm